A unified platform for converting pyridines into N-substituted heterocycles via pyridinium synthesis and functionalization

Abstract

Nitrogen-containing heterocycles, such as piperidine, are central to pharmaceuticals, agrochemicals, and functional materials, driving demand for general methods to access and diversify these scaffolds. Chapter one discusses the importance of N-substituted piperidines in pharmaceuticals and the challenges associated with accessing these heterocycles. Chapter two presents a general strategy for N-(hetero)arylpyridinium salt formation via ring-opening of pyridines and ring-closing of the corresponding NTf-Zincke imines. This method overcomes key limitations of classical approaches by enabling C2-substituted pyridines and diverse (hetero)arylamines under mild conditions, with scalable purification protocols. The resulting salts are precursors to N-(hetero)arylpiperidines and related partially saturated heterocycles via hydrogenation and reductive functionalization. In Chapter three, this platform was extended to enantioenriched N-alkylpyridinium salts from pyridines and chiral amines. Potassium metabisulfite was identified as a key additive that enhances robustness and generality through a distinct cyclication mechanism. High-throughput experimentation (HTE) demonstrated the breadth of this method in accessing diverse stereoenriched N-alkylpiperidine precursors. In Chapter four, the reactivity of pyridinium intermediates was extended to selective C4-functionalization via pyridinium sulfonate intermediates. Metabisulfite enables direct C–H sulfonation of N-substituted pyridinium salts, providing access to N-substituted pyridones and 4(1H)-pyridinylidenes in a one-pot process.